Safety and efficacy of biological agents in the treatment of Systemic Lupus Erythematosus (SLE)

Background To determine the safety and efficacy of biological agents used in the treatment of systemic lupus erythematosus (SLE) in adults. Methods Systematic review and meta-analysis following PRISMA guidelines. Data sources MEDLINE (through Pubmed), EMBASE, Cochrane library, Clinicaltrials.gov, Australianclinicaltrials.gov.au, ANZCTR.org.au and WHO International Clinical Trials Registry Platform for studies published from 20 May 2021 and 15 years prior. A grey literature search was performed and completed on 31 May 2021. Study criteria Phase II, III or quasi randomised controlled trials, studies with only cerebral or cutaneous lupus were excluded. Data extraction: Two authors independently screened studies for eligibility, extracted, reviewed data for accuracy, and used the Cochrane tool to assess risk of bias. Results Forty-four studies were identified, consisting of 15 groups of drugs and 25 different biological agents, totalling 16,889 patients. The main outcomes assessed included Systemic Lupus Erythematosus Responder Index (SRI), BILAG-Based Composite Lupus Assessment (BICLA) and combined combined/partial renal remission (CRR/PRR). Four groups of biologics were found to improve outcomes. Anti-interferons: Anifrolumab increased BICLA response and SRI 5 to 8, decreased prednisone dosages, with increased herpes zoster infections, but fewer serious adverse events. Sifalimumab improved SRI but also increased herpes zoster infections. Anti BAFF/BLyS and/or APRIL: Belimumab consistently improved SRI 4, decreased prednisone dosages, increased combined CRR/PRR, and had no adverse safety outcomes. Tabalumab increased SRI 5 at 52 weeks with no steroid sparing effect but was associated with increased infusion related adverse events. Telitacicept improved SRI 4 at 52 weeks, with no increased adverse events, though data was rather sparse. Anti CD-20 monoclonal antibody, Obinutuzumab increased combined CRR/PRR at 1 and 2 years. Anti IL12/23 monoclonal antibody, Ustekinumab, increased SRI 4 to 6, but not BICLA at 24 weeks, with no concerning safety outcomes. Conclusion Multiple biologic agents are shown in high quality studies to have a significant therapeutic impact on outcomes in SLE. Supplementary Information The online version contains supplementary material available at 10.1186/s41927-023-00358-3.


Anti-dsDNA complexing
Anti-dsDNA antibodies are one of the measured autoantibodies in SLE and form part of its diagnostic criteria.The production of anti-dsDNA antibodies in SLE are likely related to impaired tolerance to immunogenic self-DNA in SLE patients, which may mediate disease activity.Abetimus is currently the only drug in this class.

Abetimus
Abetimus is composed of 4 identical strands of dsDNA with specificity for anti-dsDNA antibodies.It is thought to function by forming drug-antibody complexes, reducing circulating anti-dsDNA antibody levels and tolerizing anti-dsDNA specific B cells.
One study consisting of 317 patients addressed the use of Abetimus in SLE: Cardiel 2008 (33).A single dose of Abetimus 100mg IV weekly for up to 22 months was studied.
The main outcome studied was time to a renal flare, which was not an outcome analysed in this review, though there was no significant difference between the Abetimus and placebo group Abetimus usage did not increase any of the adverse events studied.

Selective Janus kinase (JAK)1 and JAK2 inhibitor
JAK1 and JAK2 are tyrosine kinases that mediate intracellular pathway signalling of Type 1 and Type II cytokine receptors including interleukins and IFNs, both of which are raised in SLE, including IL-6, IL-12, IL-23, and Type 1 IFN which are being studied as potential therapeutic targets.Targeting the JAK/STAT pathway may allow suppression of these cytokines.

Baricitinib
Baricitinib is an orally administered selective and reversible inhibitor of JAK1 and JAK2.
One study addressed Baricitib use in SLE(34) recruiting 3141 patients.Patients with lupus nephritis and CNS lupus were excluded.Doses of Barictinib PO 2mg and 4mg daily were studied.Comparator treatments included continuation of previous maintenance regimens using antimalarials, AZA, MMF, MTX and steroids.
There were no significant differences in safety outcomes.

Bruton's tyrosine kinase inhibitor
BTK is expressed in B and myeloid cells, and functions as a intracellular signalling molecule involved B cell development, survival and antigen presentation and antibody production by B cell antigen receptors.BTK positive cells are increased in peripheral blood SLE patients, with higher anti-dsDNA antibody levels, proteinuria, SLEDAI scores and lower C3 levels(35).

Evobrutinib
Evobrutinib is an inhibitor of Bruton's tyrosine kinase which prevents B cell activation.
One study addressed the use of Evobrutinib in SLE: Wallace 2019 (36)which consisted of 469 patients.
Patients with CNS lupus were excluded.Evobrutinib dosages studied included 25mg QD, 75mg QD and 60mg BID PO.Comparator treatments included continuation of previous maintenance regimens.
Main study outcomes were SRI 4, SRI 6 and BICLA at 52 weeks, none which achieved significance (p=0.26,0.36 and 0.97) Infectious adverse events were not fully reported, but other safety outcomes including death did not achieve significance.
One study addressed the use of Fenebrutinib in SLE: Isenberg 2019 (36), which consisted of 260 patients.
Patients with CNS and renal involvement were excluded.Evobrutinib dosages studied included 150mg QD, and 200mg BID.Comparator treatments included continuation of previous maintenance regimens using antimalarials, AZA, MMF, MTX and steroids.
Main study outcomes studied were SRI 4, SRI 6 and BICLA at 24 weeks and 52 weeks, none which achieved significance (outcomes at 24 weeks: P=0.35, 0.69 and 0.74, at 52 weeks: P=0.30, 0.14 and 0.36 ) There were no significant differences in safety outcomes.

High-affinity cereblon ligand
Encoding transcription factors IKZF1 (Ikaros) and to a lesser extent, IKZF3 (Aiolos) polymorphisms are associated with an increased risk of SLE, and higher levels are found in SLE patients.Cullin ring ligase 4cereblon E3 ubiquitin ligase (CRL4) is an ubiquitin ligase that targets Ikaros and Aiolos for proteosomal degradation.Reductions in Ikaros and Aiolos levels is associated with decrease in B cell plasmablast differentiation, BAFF levels, CD40L induced proliferation of B-cells and IgG secretion .Currently, CC-220/Iberdomide is currently the only drug in this class.

CC-220/Iberdomide
Two studies addressed the use of CC220/Iberdomide in SLE: Gaudy 2017(37) and Merrill 2020(38) The 2 studies consisted of 330 patients, with Merrill 2020 having 288 patients.Patients with lupus nephritis and CNS lupus were excluded.Dosages of CC-220/Iberdomide are described in study protocols.
Comparator treatments included continuation of previous maintenance regimens using steroid and other immunosuppressants.Main outcomes in Gaudy 2017 were safety outcomes including adverse events and death.Merrill 2020 studied SRI 4 at 24 weeks, which did not improve with use of Iberdomide (RR 1.35, CI 0.98 to 1.88, P=0 CC-220/Iberdomide did not reduce the use of prednisone in Merrill 2020, with proportion of patients with prednisone reduction to ≤10mg/day not achieving significance (RR 0.20, CI 0.02 to 2.09, P=0.18) Adverse events were increased with CC-220/Iberdomide in Merrill 2020 , (RR 1.45, CI 1.02 to 2.06 P=0.04), with increased urinary tract, upper respiratory infections, influenza and neutropaenia, but not in the pooled data of both studies or Gaudy 2017 (Figure 19).Treatment related adverse events were increased with CC-220/Iberdomide RR1.39, CI 1.02 to 1.90, P=0.04) (Figure 23).There were no significant differences in the other safety outcomes in both studies.

Tolerogenic peptides Edratide
Edratide is a tolerogenic peptide based on the complementarity-determining region 1 (CDR1) of a human anti-DNA mAb.Murine models treated with Edrateide showed a decrease in IFN-Y, IL-10 and IL-1B, BAFF/BLyS and an increase in CD4 and CD8 regulatory T cells.
One study addressed the used of Edratide in SLE: Urowitz 2015 (39), including 340 patients.Patients with CNS lupus, lupus nephritis and using any immunosuppressants aside from prednisone were excluded.
Edratide dosage are described in study protocols.Comparator treatments only allowed for prednisone, antimalarials and NSAIDs.
The main outcomes studied were BILAG and SLEDAI improvement, which were not analysed in this review, though both outcomes were not increased with the use of Edratide compared to placebo.
Edratide use did not increase adverse events and death.
Anti CD22 monoclonal antibody B cells exclusively express CD22 (Siglec-2), which have been shown to inhibit B-cell receptor signalling. 2 immunoregulatory tyrosine-activating motifs and/or immunoregulatory tyrosine-inhibiting motifs (ITIMs) on CD22 recruit PTP and SHP-1 which when phosphrylated forms a SHIP complex and activation of MAP kinase which regulates cell survival and proliferation.Epratuzumab is the only drug in this class tested in SLE patients.

Epratuzumab
Epratuzumab is a humanized IgG monoclonal antibody against CD22, derived from the murine IgG2 monoclonal antibody.
Epratuzumab dosages are summarised in the study protocols.Comparator treatments included continuation of previous maintenance regimens using steroid and other immunosuppressants.
Main study outcomes were SRI 4 and BICLA response.
In the pooled data of all the dosages, Epratuzumab did not increase BICLA response, at 12 weeks in EMBLEM (RR 1.90, CI 0.83 to 4.39, P=0.13) and 52 weeks in EMBODY 1 /2 (RR 1.08, CI 0.94 to 1.25, P=0.29) Epratuzumab use did not increase SRI 4 at 52 weeks (RR 1.05, CI 0.91 to 1.22, P=0.51) in Clowse 2017.There were no significant differences in the reported safety outcomes.
Anti-interleukin (IL) 6 antibody IL-6 levels are shown to be higher in patients with SLE compared to healthy patients, in active compared to inactive SLE .B cells and T cells in SLE also express higher levels of IL-6.CNS lupus patients are also found to have higher CSF levels of IL-6, and urinary IL-6 elevation correlate with lupus nephritis disease activity and anti-dsDNA titres.

PF-04236921
PF-04236921 is a fully human immunoglobulin G2 monoclonal antibody that binds to IL-6.
One There were no significant differences in the other reported safety outcomes.

Vobarilizumab
Vobarilizumab is an anti IL-6 nanobody that binds to and neutralises human IL-6.
One study addressed the use of Vobarilizumab in SLE: NCT0243789 (44) , consisting of 312 patients.
Patients with lupus nephritis and CNS lupus were excluded.Vobarilizumab dosages are summarised in the study protocols.Comparator treatments included continuation of previous maintenance regimens using antimalarials, AZA, MMF, MTX and steroids.
The main study outcome was SRI responses at weeks 24 and 52.Vobarilizumab did not increase SRI 4 to 8 at weeks 24 and 52, with P-values ranging from 0.2 to 1.0.There were no significant differences in the safety outcomes.
Anti Interleukin-10 monoclonal antibody IL-10 levels are increased in patients with SLE and correlates with disease activity, with the majority being produced monocytes, B lymphocytes and a smaller extent, from T lymphocytes.The constant presence of autoantibodies such as anti-dsDNA may allow for B cells to be continuously primed for IL-10 costimulation, promoting B cell differentiation and further autoantibody production .BT063 is currently the only drug in this class.

BT063
BT063 is a humanised anti IL-10 monoclonal antibody.It has currently only been studied in SLE.
One study addressed the use of BT063 in SLE: NCT02554019 (45) consisting of 36 patients.Patients with active and severe lupus nephritis or neuropsychiatric lupus were excluded.Dosages of 50 and 100mg were studied.Comparator treatments allowed for continuation of previous maintenance regimens.
The main outcomes consisted of safety outcomes.Adverse and serious adverse events, withdrawal due to adverse events and death were not increased with BT063 P140 peptide P140 peptide containing a phosphoserine residue at position 140 formed from spliceosomal U1-70K small nuclear ribonucloproteins which interacts with the HSC70/Hsp73 protein.In MRL/lpr murine models, P140 decreased the expression and folding of HSC70 chaperone proteins and down regulated lysosomal degradation during autophagic flux, possibly decreasing the presentation of self antigens to autoreactive T cells.
Lupuzor Lupuzor usage did not increase death, serious adverse events and withdrawal due to adverse events.

Recombinant, soluble human FcγRIIb
Immune complexes produced in autoimmune diseases are able to activate FcyRs which stimulate secretion of inflammatory cytokines such as TNF-alpha and IL-6.FcyRIIb is an inhibitory Fc receptor and has been shown to decrease inflammatory cytokines and IgG autoantibodies in murine models for inflammatory arthritis.

SM101
SM101 is a recombinant soluble FcγIIb receptor which binds to the Fc part of immune complexes, inhibiting the binding of immune complexes to cell-standing Fcg receptors.It was previously studied in immune thrombocytopenic purpura but not currently indicated in its treatment.
One study addressed the use SM101 in SLE: Tillmans 2014 (48) which consisted of 51 patient.Patients with lupus nephritis were included, though the class/severity were not stated.SM101 dosages of 6 and 12mg/kg were studied.Comparator treatments included continuation of AZA, MMF and steroids.
The main outcome studied was SRI 4 at 24 weeks, which was not increased with SM101 (RR 2.06, CI 0.55 to 7.69, P= 0.28).No safety data was reported in this small study.
Merrill 2012 (Belimumab) -Long term follow up study of Wallace 2009 Belimumab study.extension study, patients no longer randomised as they entered an open label study Ginzler 2014 (Belimumab)-Long term follow up of Wallace 2009 study at 4 years, only follows intervention arm but not placebo/control arm Tanaka 2017 (Belimumab) -Subset of Zhang 2018 paper Aranow 2018 -Abstract of Atisha Fregoso 2021 CALIBRATE study Doria 2018 (Belimumab) -Subset of Stohl 2017 Belimumab paper Furie 2018 (Belimumab) -Long term study of BLISS-76 paper , only follows up intervention arm with Belimumab without comparison placebo/control arm Furie 2020 NOBILITY (Obinutuzumab)-2nd year extension data from Furie 2019 paper, data amalgamated into Furie 2019 outcomes Rovin 2020 (Obinutuzumab) -Subset of Furie 2019 , looking at response at 76 weeks depending on B cell depletion status Vital 2020 (Obinutuzumab)-Subset of Furie 2019 Nobility study.Looks to be a duplicate of Rovin 2020 abstract as well Not fulfilling study criteria Arienger 2009 -Follow up of patients on infliximab only, not RCT Baker 2020 -Not a randomised trial, compared either filgotinib or lanraplenib, no placebo arm Decreux 2016-Testing only on patient serum samples, not a clinical trial.Not randomised/no control arm/non clinical trial Dooley 2016 -Voclosporin not a biologic Fernandez 2006 -Rapamycin not a biologic agent Furie 2001 -Beyond data collection period of 15 years Hasni 2019 -Phase 1b study, abstract only Llorente 2000 -Study on sle patients, but no controls, not a clinical trial Masoud 2018 -Case report series of Ofatumumab, not a randomised trial Merrill 2018 XmAb®5871 -No data published NCT02847598 BIIB059 -studying cutaneous lupus with/without other lupus manifestations.no data yet as well NCT03159936 Tofacitinib -study only discoid lupus patients only Reddy Obitunuzumab 2017 -not clinical trial, study performed only on patient blood samples to study B cell cytotoxicity Rovin 2018 -voclosporin not a biologic Shi R Lulizumab 2019 -Pharmacokinetic,pharmacodynamic, not phase 2/3 RCT study, and in healthy subjects without SLE Streicher 2018 -not a clinical trial, studying skin biopsy samples from other trials, also includes disease other than SLE in study (COPD) This review was conducted according to the PRISMA check list.MEDLINE (through Pubmed), EMBASE, the Cochrane library, and Clinicaltrials.gov,Australianclinicaltrials.gov, ANZCTR.gov and WHO International Clinical Trials Regsitry Platform were searched on 20 May 2021, using the search terms (Medical Subject Heading (MeSH), EMTREE and/or free text) for (I) Clinical trials (II) Randomized control trials and (III) systemic lupus erythematosus (systemic lupus, lupus, and SLE) (IV) Biologic/Biological agents (monoclonal antibodies,).Search terms within (I) and (II) were combined using 'OR', and both groups of search terms combined with 'AND' (III and IV).Search results were limited to human clinical trials in English, published within 15 years, for which full-text articles were available for appraisal.All MeSH and EMTREE terms were exploded.A grey literature search was conducted, all data collected was initially completed by 30 May 2021.